Potential Determinants of Low Circulating Glucagon‐like Peptide 2 Concentrations in Zambian Children with Non‐responsive Stunting

Abstract Nutrient sensing determines digestive and hormonal responses following nutrient ingestion. We have previously reported decreased levels of glucagon‐like peptide 2 (GLP‐2) in children with stunting. Here we demonstrate the presence of enteroendocrine cells in stunted children and explore potential pathways that may be involved in reduced circulating levels of GLP‐2. At the time of performing diagnostic endoscopies for non‐responsive stunted children, intestinal biopsies were collected for immunofluorescence staining of enteroendocrine cells and transcriptomic analysis. Circulating levels of GLP‐2 were also measured and correlated with transcriptomic data. An exploratory genome‐wide association study (GWAS) was conducted on DNA samples (n = 158) to assess genetic contribution to GLP‐2 variability. Intestinal tissue sections collected from non‐responsive stunted children stained positive for chromogranin A (88/89), alongside G‐protein‐coupled receptors G‐protein receptor 119 (75/87), free fatty acid receptor 3 (76/89) and taste 1 receptor 1 (39/45). Transcriptomic analysis found three pathways correlated with circulating GLP‐2: sugar metabolism, epithelial transport, and barrier function, which likely reflect downstream events following receptor–ligand interaction. GWAS analysis revealed potential genetic contributions to GLP‐2 half‐life and receptor binding. Enteroendocrine cell loss was not identified in stunted Zambian children as has been observed for goblet and Paneth cells. Transcriptomic analysis suggests that GLP‐2 has pleiotrophic actions on the intestinal mucosa in malnutrition, but further work is needed to dissect pathways leading to perturbations in nutrient sensing.